博文
【原创】Clin Cancer Res：全新膀胱癌标志物及其BCMab1单抗
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膀胱癌为泌尿系最常见的恶性肿瘤，发病率在美国被列为男性恶性肿瘤的第四位，在我国列为泌尿系肿瘤第一位。膀胱癌约95％来源于膀胱上皮，包括乳头状瘤、移行细胞癌、鳞状细胞癌和腺癌。绝大多数为恶性，其中以移行细胞癌最常见，占80%以上。预后较差和极易复发是膀胱癌的最大特点，有效的治疗将有赖于发现特异性高的膀胱癌肿瘤标志物。通过多年努力，我们筛选到了一株高特异性的抗膀胱癌单克隆抗体BCMab1，BCMab1单抗识别的抗原表位是异常糖基化修饰的整合素a3b1（AG-a3b1），是一个全新的膀胱癌肿瘤标志物。并证实异常糖基化修饰的整合素a3b1只表达于人膀胱肿瘤的细胞膜上，并与膀胱癌的肿瘤分期和病理分级呈正相关。BCMab1单抗特异性识别异常糖基化修饰的整合素a3b1分子，能有效地抑制肿瘤细胞的增殖、迁移、粘附和侵袭。该BCMab1抗体通过ADCC和ADCP作用，介导NK细胞和巨噬细胞对肿瘤的清除作用。BCMab1单抗膀胱灌注裸鼠原位模型能够明显抑制肿瘤的生长。经BCMab1单抗给药的动物均没有出现全身及局部的毒副作用。该研究显示：BCMab1抗体具有很强的抑制肿瘤生长的能力。
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BCMab1, a monoclonal antibody against aberrantly glycosylated integrin α3β1, has potent antitumor activity of bladder cancer in vivo.
To identify a novel biomarker for bladder cancer targeting therapy.
EXPERIMENTAL DESIGN:The human bladder cancer cell line T24 cells were used as immunogen to generate mousemonoclonal antibodies. We screened and identified a specific antibody BCMab1 against bladder cancer. We examinedBCMab1 antigen expression in the patients with bladder cancer through immunohistochemical staining and investigated the BCMab1 antigen association with clinical severity. We detected the antitumor activity of BCMab1antibody and investigated its therapeutic efficacy by subcutaneous and orthotopic bladder cancer models.
RESULTS:We developed a new monoclonal antibody BCMab1 against bladder cancer that specifically recognized theaberrantly glycosylated Integrin α3β1 epitope on bladder cancer cells. Expression of the BCMab1 antigen was consistent with clinical severity and prognosis of bladder cancer. The glycosyltransferase GALNT1 could contribute to aberrant glycosylation of Integrin α3. The aberrant glycosylation of integrin α3-activated integrin signaling to initiate FAK activation. BCMab1 could block Integrin engagement to inhibit its signaling leading to cell-cycle arrest. In addition, BCMab1 enhanced FcγR-dependent antitumor activity in vivo.
CONCLUSIONS:BCMab1 antigen is a new biomarker for bladder cancer. BCMab1 antibody exhibited potent antitumor activity against bladder cancer in vivo.
©2014 American Association for Cancer Research.
https://blog.sciencenet.cn/blog-3227923-999548.html
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